Novel compounds

ABSTRACT

The present invention relates to substituted indoles useful as pharmaceutical compounds for treating respiratory disorders.

The present invention relates to substituted indoles useful aspharmaceutical compounds for treating respiratory disorders,pharmaceutical compositions containing them, and processes for theirpreparation.

EPA 1 170 594 discloses methods for the identification of compoundsuseful for the treatment of disease states mediated by prostaglandin D2,a ligand for orphan receptor CRTh2. U.S. Pat. No. 5,486,525 discloses aseries of indoles said to possess PAF antagonist activity. It has nowsurprisingly been found that certain indole acetic acids are active atthe CRTh2 receptor, and as a consequence are expected to be potentiallyuseful for the treatment of various respiratory diseases, includingasthma and COPD.

In a first aspect the invention therefore provides a compound of formula(I) or a pharmaceutically acceptable salt and solvates thereof:

in which:R¹ is one or more substituents independently selected from NR⁴SO₂R⁵,NR⁴CO₂R⁶, NR⁴COR⁶, NR⁴SO₂NR⁵R⁶, NHSO₂R⁵, NHCO₂R⁶, NHCOR⁶, NHCONR⁴,NHSO₂NR⁵R⁶, or heteroaryl, the latter which may be optionallysubstituted by halogen, CN, OR⁷, C₁₋₃ alkyl (which may be optionallysubstituted by halogen atoms);R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, CH₂OH, CH₂OR⁴ orC₁₋₄alkyl, the latter group being optionally substituted by one or moresubstituents independently selected from halogen atoms, OR⁸ and NR⁵R⁶,S(O)_(x)R⁷ where x is 0, 1 or 2;R³ is aryl or heteroaryl each of which is optionally substituted by oneor more substituents independently selected from hydrogen, halogen, CN,OH, SO₂R⁴, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NHSO₂R⁴, NHCOR⁴,NHCO₂R⁴, NR⁷SO₂R⁴, NR⁷CO₂R⁴, NR⁷COR⁴, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁₋₆alkyl, the latter three groups being optionally substituted by one ormore substituents independently selected from halogen atoms, OR⁸ andNR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1 or 2;R⁴ represents aryl, heteroaryl, or C₁₋₆alkyl all of which may beoptionally substituted by one or more substituents independentlyselected from halogen atoms, aryl, heteroaryl, OR¹⁰, OH, NR¹¹R¹²,S(O)_(x)R¹³ (where x is 0, 1 or 2), CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵,NR¹⁴SO₂R¹⁵, CN, nitro;R⁵ and R⁶ independently represent a hydrogen atom, a C₁₋₆ alkyl group,or an aryl, or a heteroaryl, the latter three of which may be optionallysubstituted by one or more substituents independently selected fromhalogen atoms, aryl, OR⁸ and NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵,NR¹⁴SO₂R¹⁵; K CN, nitro, C₁₋₃ alkyl (which may be optionally substitutedby halogen atoms; orR⁵ and R⁶ together with the nitrogen atom to which they are attached canform a 3-8 membered saturated heterocylic ring optionally containing oneor more atoms selected from O, S(O)_(x), where x is 0, 1 or 2, NR¹⁶, anditself optionally substituted by C₁₋₃ alkyl;R⁷ and R¹³ independently represent a C₁-C₆, alkyl, an aryl or aheteroaryl group, all of which may be optionally substituted by halogenatoms;R⁸ represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl (optionallysubstituted by halogen atoms or aryl) an aryl or a heteroaryl group(optionally substituted by halogen);each of R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, independently represents a hydrogenatom, C₁-C₆ alkyl, an aryl or a heteroaryl group (all of which may beoptionally substituted by halogen atoms); andR¹⁶ is hydrogen, C₁₋₄ alkyl, COC₁-C₄ alkyl or COYC₁-C₄alkyl where Y is Oor NR⁷.

in the context of the present specification, unless otherwise indicated,an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituentgroup may be linear, branched or cyclic.

Aryl groups as defined herein can be phenyl or naphthyl.

Heteroaryl is defined as a 5-7 membered aromatic ring or can be 6,6- or6,5-fused bicyclic, each ring containing one or more heteroatomsselected from N, S and O. Examples include pyridine, pyrimidine,thiazole, oxazole, pyrazole, imidazole, furan, isoxazole, pyrrole,isothiazole and azulene, naphthyl, indene, quinoline, isoquinoline,indole, indolizine, benzo[b]furan, benzo[b]thiophene, 1H-indazole,benzimidazole, benzthiazole, benzoxazole, purine, 4H-quinolizine,cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine,pteridine, quinolone.

When R⁵ and R⁶ together with the nitrogen atom to which they areattached can form a 3-8 membered saturated heterocylic ring, examplesinclude morpholine, thiomorpholine, azetidine, imidazolidine,pyrrolidine, piperidine and piperazine. Substituents can be present oncarbon or appropriate nitrogen atoms of such rings.

Suitably R¹ is one or more substituents independently selected fromNR⁴SO₂R⁵, NR⁴CO₂R⁶, NR⁴COR⁶, NR⁴SO₂NR⁵R⁶, NHSO₂R⁵, NHCO₂R⁶, NHCOR⁶,NHCONR⁴, NHSO₂NR⁵R⁶, or heteroaryl, the latter which may be optionallysubstituted by halogen, CN or OR⁷.

Suitably R¹ is one or more substituents independently selected fromNR⁴SO₂R⁵, NR⁴CO₂R⁶, NR⁴COR⁶, NR⁴SO₂NR⁵R⁶, NHSO₂R⁵, NHCO₂R⁶, NHCOR⁶,NHSO₂NR⁵R⁶, or heteroaryl, the latter which may be optionallysubstituted by halogen, CN or OR⁷.

Preferably R¹ is NR⁴COR⁶⁴, NHSO₂R⁴, NHCOR⁶ or a heteroaryl group.

More preferably R¹ is NHSO₂Me or NR⁴COMe, NHCONHalkyl, NR⁴COcyclopropyl,NHSO₂heteroaryl, NHSO₂NMe₂, NHCONR⁴, a 5-6 membered heteroaromatic groupcontaining 1-2 heteroatoms. Most preferably R¹ is NHSO₂Me or NR⁴COMe,NHCONHalkyl, dimethyoxazole, pyrimidine or pyrazine. Even morepreferably R¹ is NHCOMe.

The R¹ groups can be present at any suitable position on the indolering. Preferably the R¹ group(s) is (are) at the 5-position and/or4-position.

Preferably R² is C₁₋₆alkyl or hydrogen, more preferably C₁₋₆alkyl orhydrogen, still more preferably methyl or hydrogen. Most preferably R²is methyl.

Preferably R³ is quinolyl or phenyl, the latter is optionallysubstituted by halogen, alkoxy, SO₂R⁴, more preferably the phenyl groupis substituted by chloro, methoxy, methylsulfone or ethylsulfone.

Substituents can be present on any suitable position of an R³ group.Preferably, if R³ is phenyl the substituents is/are present at the 2, 3and 4-positions. Most preferably a single substituent is present at the4-position.

Preferred compounds of the invention include:

-   4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic    acid;-   3-[(2-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(3-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(3-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(4-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(2-trifluoromethylphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(8-Quinolinyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   3-[(2-(methylethyl)phenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic    acid;-   5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic    acid;-   4-(acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-1-acetic    acid;-   4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic    acid;-   4-(acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-indole-1-acetic    acid;-   4-(acetylamino)-2-methyl-3-[(4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid;-   4-(acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic    acid;-   4-(acetylamino)-2-methyl-3-[[(4-(ethylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid;-   3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)carbonyl]amino]-2-methyl-1H-indole-1-acetic    acid;-   3-[[(4-(methylsulfonyl)phenyl]thio]-4-(5-primidinyl)-1H-indole-1-acetic    acid-   2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indole-1-acetic    acid-   4-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid-   4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid-   2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid-   2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid-   2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid-   2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-acetic    acid-   2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-thiophenyl)-1H-indole-1-acetic    acid-   5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic    acid-   2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-acetic    acid-   2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indole-1-acetic    acid-   4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic    acid    and pharmaceutically acceptable salts and solvates thereof.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

The compound of formula (I) above may be converted to a pharmaceuticallyacceptable salt or solvate thereof, preferably a basic addition saltsuch as ammonium, sodium, potassium, calcium, aluminium, lithium,magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine,ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or anacid addition salt such as a hydrochloride, hydrobromide, phosphate,acetate, fumarate, maleate, tartrate, citrate, oxalate,methanesulphonate or p-toluenesulphonate. Preferred salts include sodiumand ammonium salts.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups in the startingreagents or intermediate compound may need to be protected by protectinggroups. Thus, the preparation of the compound of formula (I) mayinvolve, at an appropriate stage, the removal of one or more protectinggroups. The protection and deprotection of functional groups is fullydescribed in ‘Protective Groups in Organic Chemistry’, edited by J. W.F. McOmie, Plenum Press (1973), and ‘Protective Groups in OrganicSynthesis’, 3rd edition, T. W. Greene & P. G. M. Wuts,Wiley-Interscience (1999).

In a further aspect the invention provides a process for the preparationof a compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof which comprises reaction of a compound of formula (II):

in which R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof, with a compound of formula (IIA):

L-CH₂CO₂R¹⁷  (IIA)

where R¹⁷ is an alkyl group and L is a leaving group such as a halogenatom, in the presence of a base, and optionally thereafter in any order:

-   -   removing any protecting group    -   hydrolysing the ester group R¹⁷ to the corresponding acid    -   forming a pharmaceutically acceptable salt or solvate.

The reaction can be carried out in a suitable solvent such as THF usinga base such as sodium hydride or the like. Suitable groups R¹⁷ includeC₁₋₆ alkyl groups such as methyl, ethyl or tertiary-butyl. Suitable L isa leaving group such as halo, in particular bromo Preferably thecompound of formula (IIA) is ethyl, methyl or tertiary-butylbromoacetate.

Hydrolysis of the ester group R¹⁷ can be carried out using routineprocedures, for example by stirring with aqueous sodium hydroxide ortrifluoroacetic acid.

It will be appreciated that certain functional groups may need to beprotected using standard protecting groups. The protection anddeprotection of functional groups is for example, described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 3rdedition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1999).

Compounds of formula (II), in which R¹ is NRSO₂R or NRC(O)R can be fromcompounds of formula by reaction with an acylating reagent such asacetyl chloride or sulfonyl chloride.

Compounds of formula (III) can be prepared from compounds of formula(IV) by reduction using a hydrogen and a suitable catalyst, preferably,the catalyst used is palladium or platinum on activated carbon in thepresence of a polar solvent such as ethanol.

Compounds of formula (IV) can be prepared from compounds of formula (V)and (VI)

in which R¹, R² and R³ are as defined in formula (I).

Preferably the reaction is carried out in a suitable solvent, such asdichloromethane or THF, using a chlorinating agent such as sulfonylchloride or tert-butyl hypochlorite.¹

Compounds of formulae (V) and (VI) are commercially available or can beprepared using standard chemistry well known in the art.

Certain compounds of formula (I) can be prepared from compounds offormula (VII) where X=halogen, preferably bromine or iodine, by reactionwith organostannanes (Stille couplings) or boronic acids (Suzukicouplings) using palladium catalysis. Preferably the catalysts used aretetrakis palladium triphenylphosphine(0), or palladium(II) acetate inthe presence of a phosphine ligand such as tri-ortho tolyl phosphine, ina suitable solvent such as toluene or methanol at 80° C. The group R¹⁷is subsequently hydrolysed as outlined previously.

Compounds of formula (VII) are prepared from compounds of formula (II)with compounds of formula (IIA) as outlined previously:

Compounds of formula (II), where X is halogen are prepared by reacting acompound of formula (VIII) with a compound of formula (VI):

in which R¹, R² and R³ are as defined in formula (I).

Compounds of formula (II) can be prepared by reacting a compound offormula (IX) with a compound of formula (X), with subsequent hydrolysisof the ester as outlined previously for the synthesis of compounds offormula (I):

in which R¹, R² and R³ or protected derivatives thereof, are as definedin formula (I). The reaction is carried out in a suitable solvent in thepresence of a halogen, preferably iodine at room temperature, in a polaraprotic solvent, for example DMF. Compounds of formula (IX) and (X) arecommercially available or can be prepared by methods well known in theart.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of CRTh2 receptor activity, and may be used inthe treatment (therapeutic or prophylactic) of conditions/diseases inhuman and non-human animals which are exacerbated or caused by excessiveor unregulated production of PGD₂ and its metabolites.

A compound of the invention, or a pharmaceutically acceptable saltthereof, can be used in the treatment of:

-   -   (1) (respiratory tract)—obstructive diseases of the airways        including: asthma, including bronchial, allergic, intrinsic,        extrinsic, exercise-induced, drug-induced (including aspirin and        NSAID-induced) and dust-induced asthma, both intermittent and        persistent and of all severities, and other causes of airway        hyper-responsiveness; chronic obstructive pulmonary disease        (COPD); bronchitis, including infectious and eosinophilic        bronchitis; emphysema; bronchiectasis; cystic fibrosis;        sarcoidosis; farmer's lung and related diseases;        hypersensitivity pneumonitis; lung fibrosis, including        cryptogenic fibrosing alveolitis, idiopathic interstitial        pneumonias, fibrosis complicating anti-neoplastic therapy and        chronic infection, including tuberculosis and aspergillosis and        other fungal infections; complications of lung transplantation;        vasculitic and thrombotic disorders of the lung vasculature, and        pulmonary hypertension; antitussive activity including treatment        of chronic cough associated with inflammatory and secretory        conditions of the airways, and iatrogenic cough; acute and        chronic rhinitis including rhinitis medicamentosa, and vasomotor        rhinitis; perennial and seasonal allergic rhinitis including        rhinitis nervosa (hay fever); nasal polyposis; acute viral        infection including the common cold, and infection due to        respiratory syncytial virus, influenza, coronavirus (including        SARS) and adenovirus.    -   (2) (bone and joints) arthritides associated with or including        osteoarthritis/osteoarthrosis, both primary and secondary to        e.g. congenital hip dysplasia; cervical and lumbar spondylitis,        and low back and neck pain; rheumatoid arthritis and Still's        disease; seronegative spondyloarthropathies including ankylosing        spondylitis, psoriatic arthritis, reactive arthritis and        undifferentiated spondarthropathy; septic arthritis and other        infection-related arthopathies and bone disorders such as        tuberculosis, including Potts' disease and Poncet's syndrome;        acute and chronic crystal-induced synovitis including urate        gout, calcium pyrophosphate deposition disease, and calcium        apatite related tendon, bursal and synovial inflammation;        Behcet's disease; primary and secondary Sjogren's syndrome;        systemic sclerosis and limited scleroderma; systemic lupus        erythematosus, mixed connective tissue disease, and        undifferentiated connective tissue disease; inflammatory        myopathies including dermatomyositits and polymyositis;        polymalgia rheumatica; juvenile arthritis including idiopathic        inflammatory arthritides of whatever joint distribution and        associated syndromes, and rheumatic fever and its systemic        complications; vasculitides including giant cell arteritis,        Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis        nodosa, microscopic polyarteritis, and vasculitides associated        with viral infection, hypersensitivity reactions, cryoglobulins,        and paraproteins; low back pain; Familial Mediterranean fever,        Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi        disease; drug-induced arthalgias, tendonititides, and        myopathies.    -   (3) (skin) psoriasis, atopic dermatitis, contact dermatitis or        other eczematous dermatoses, and delayed-type hypersensitivity        reactions; phyto- and photodermatitis; seborrhoeic dermatitis,        dermatitis herpetiformis, lichen planus, lichen sclerosus et        atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus        erythematosus, pemphigus, pemphigoid, epidermolysis bullosa,        urticaria, angioedema, vasculitides, toxic erythemas, cutaneous        eosinophilias, alopecia greata, male-pattern baldness, Sweet's        syndrome, Weber-Christian syndrome, erythema multiforme;        cellulitis, both infective and non-infective; panniculitis;        cutaneous lymphomas, non-melanoma skin cancer and other        dysplastic lesions; drug-induced disorders including fixed drug        eruptions.    -   (4) (eyes) blepharitis; conjunctivitis, including perennial and        vernal allergic conjunctivitis; iritis; anterior and posterior        uveitis; choroiditis; autoimmune; degenerative or inflammatory        disorders affecting the retina; ophthalmitis including        sympathetic ophthalmitis; sarcoidosis; infections including        viral, fungal, and bacterial.    -   (5) (gastrointestinal tract) glossitis, gingivitis,        periodontitis; oesophagitis, including reflux; eosinophilic        gastro-enteritis, mastocytosis, Crohn's disease, colitis        including ulcerative colitis, proctitis, pruritic ani; coeliac        disease, irritable bowel syndrome, and food-related allergies        which may have effects remote from the gut (for example        migraine, rhinitis or eczema).    -   (6) (abdominal) hepatitis, including autoimmune, alcoholic and        viral; fibrosis and cirrhosis of the liver; cholecystitis;        pancreatitis, both acute and chronic.    -   (7) (genitourinary) nephritis including interstitial and        glomerulonephritis; nephrotic syndrome; cystitis including acute        and chronic (interstitial) cystitis and Hunner's ulcer; acute        and chronic urethritis, prostatitis, epididymitis, oophoritis        and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile        dysfunction (both male and female).    -   (8) (Allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin or cornea or following blood transfusion; or        chronic graft versus host disease;    -   (9) (CNS) Alzheimer's disease and other dementing disorders        including CJD and nvCJD; amyloidosis; multiple sclerosis and        other demyelinating syndromes; cerebral atherosclerosis and        vasculitis; temporal arteritis; myasthenia gravis; acute and        chronic pain (acute, intermittent or persistent, whether of        central or peripheral origin) including visceral pain, headache,        migraine, trigeminal neuralgia, atypical facial pain, joint and        bone pain, pain arising from cancer and tumor invasion,        neuropathic pain syndromes including diabetic, post-herpetic,        and HTV-associated neuropathies; neurosarcoidosis; central and        peripheral nervous system complications of malignant, infectious        or autoimmune processes.    -   (10) Other auto-immune and allergic disorders including        Hashimoto's thyroiditis, Graves' disease, Addison's disease,        diabetes mellitus, idiopathic thrombocytopaenic purpura,        eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid        syndrome.    -   (11) Other disorders with an inflammatory or immunological        component; including acquired immune deficiency syndrome (AIDS),        leprosy, Sezary syndrome, and paraneoplastic syndromes.    -   (12) (Cardiovascular); atherosclerosis, affecting the coronary        and peripheral circulation; pericarditis; myocarditis,        inflammatory and auto-immune cardiomyopathies including        myocardial sarcoid; ischaemic reperfusion injuries;        endocarditis, valvulitis, and aortitis including infective (e.g.        syphilitic); vasculitides; disorders of the proximal and        peripheral veins including phlebitis and thrombosis, including        deep vein thrombosis and complications of varicose veins.    -   (13) (Oncology) treatment of common cancers including prostate,        breast, lung, ovarian, pancreatic, bowel and colon, stomach,        skin and brain tumors and malignancies affecting the bone marrow        (including the leukaemias) and lymphoproliferative systems, such        as Hodgkin's and non-Hodgkin's lymphoma; including the        prevention and treatment of metastatic disease and tumour        recurrences, and paraneoplastic syndromes.    -   (14) Diseases associated with raised levels of PGD₂ or its        metabolites.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

Preferably the compounds of the invention are used to treat diseases inwhich the chemokine receptor belongs to the CRTh2 receptor subfamily.

Particular conditions which can be treated with the compounds of theinvention are asthma, rhinitis and other diseases in which raised levelsof PGD₂ or its metabolites. It is preferred that the compounds of theinvention are used to treat asthma.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy in particular for the treatment of adisease mediated by CRTh2 such as asthma or rhinitis.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

Preferably the compounds of the invention are used to treat diseases inwhich the chemokine receptor belongs to the CRTh2 receptor subfamily.

Particular conditions which can be treated with the compounds of theinvention are asthma, rhinitis and other diseases in which raised levelsof PGD₂ or its metabolites. It is preferred that the compounds of theinvention are used to treat asthma.

The invention further relates to combination therapies wherein acompound of formula (I) or a pharmaceutically acceptable salts, solvateor in vivo hydrolysable ester thereof, or a pharmaceutical compositionor formulation comprising a compound of formula (I) is administeredconcurrently or sequentially with therapy and/or an agent for thetreatment of any one of asthma, allergic rhinitis, cancer, COPD,rheumatoid arthritis, psoriasis, inflammatory bowel diseases,osteoarthritis or osteoporosis.

In particular, for the treatment of the inflammatory diseases rheumatoidarthritis, psoriasis, inflammatory bowel disease, COPD, asthma andallergic rhinitis the compounds of the invention may be combined withagents such as TNF-α inhibitors such as anti-TNF monoclonal antibodies(such as Remicade, CDP-870 and D₂E₇.) and TNF receptor immunoglobulinmolecules (such as Enbrel.reg.), non-selective COX-1/COX-2 inhibitors(such as piroxicam, diclofenac, propionic acids such as naproxen,flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such asmefenamic acid, indomethacin, sulindac, apazone, pyrazolones such asphenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such asmeloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib) low dosemethotrexate, lefunomide; ciclesonide; hydroxychloroquine,d-penicillamine, auranofin or parenteral or oral gold.

The present invention still further relates to the combination of acompound of the invention together with a leukotriene biosynthesisinhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activatingprotein (FLAP) antagonist such as zileuton; ABT-761; fenleuton;tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compoundSB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such asL-739,010; 2-cyanoquinoline compounds such as L-746,530; indole andquinoline compounds such as MK-591, MK-886, and BAY x 1005.

The present invention still further relates to the combination of acompound of the invention together with a receptor antagonist forleukotrienes LTB₄, LTC₄, LTD₄, and LTE₄. selected from the groupconsisting of the phenothiazin-3-ones such as L-651,392; amidinocompounds such as CGS-25019c; benzoxalamines such as ontazolast;benzenecarboximidamides such as BBL 284/260; and compounds such aszafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention together with a PDE4 inhibitor includinginhibitors of the isoform PDE4D.

The present invention still further relates to the combination of acompound of the invention together with a antihistaminic H₁. receptorantagonists such as cetirizine, loratadine, desloratadine, fexofenadine,astemizole, azelastine, and chlorpheniramine.

The present invention still further relates to the combination of acompound of the invention together with a gastroprotective H₂. receptorantagonist.

The present invention still further relates to the combination of acompound of the invention together with an α₁- and α₂-adrenoceptoragonist vasoconstrictor sympathomimetic agent, such as propylhexedrine,phenylephrine, phenylpropanolamine, pseudoephedrine, naphazolinehydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, and ethylnorepinephrinehydrochloride.

The present invention still further relates to the combination of acompound of the invention together with anticholinergic agents such asipratropium bromide; tiotropium bromide; oxitropium bromide;pirenzepine; and telenzepine.

The present invention still further relates to the combination of acompound of the invention together with a β₁- to β₄-adrenoceptoragonists such as metaproterenol, isoproterenol, isoprenaline, albuterol,salbutamol, formoterol, salmeterol, terbutaline, orciprenaline,bitolterol mesylate, and pirbuterol; or methylxanthanines includingtheophylline and aminophylline; sodium cromoglycate; or muscarinicreceptor (M1, M2, and M3) antagonist.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the invention together with an inhaled glucocorticoid withreduced systemic side effects, such as prednisone, prednisolone,flunisolide, triamcinolone acetonide, beclomethasone dipropionate,budesonide, fluticasone propionate, and mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-12.

The present invention still further relates to the combination of acompound of the invention together with other modulators of chemokinereceptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1,CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for theC—X₃—C family.

The present invention still further relates to the combination of acompound of the invention together with antiviral agents such asViracept, AZT, aciclovir and famciclovir, and antisepsis compounds suchas Valant.

The present invention still further relates to the combination of acompound of the invention together with cardiovascular agents such ascalcium channel blockers, lipid lowering agents such as statins,fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptorantagonists and platelet aggregation inhibitors.

The present invention still further relates to the combination of acompound of the invention together with CNS agents such asantidepressants (such as sertraline), anti-Parkinsonian drugs (such asdeprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine andrasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopaminereuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamineagonists and inhibitors of neuronal nitric oxide synthase), andanti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors,propentofylline or metrifonate.

The present invention still further relates to the combination of acompound of the invention together with (i) tryptase inhibitors; (ii)platelet activating factor (PAF) antagonists; (iii) interleukinconverting enzyme (ICE) inhibitors; (iv) 1 MPDH inhibitors; (v) adhesionmolecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii)MAP kinase inhibitors; (viii) glucose-6 phosphate dehydrogenaseinhibitors; (ix) kinin-B.sub1.- and B.sub2.-receptor antagonists; (x)anti-gout agents, e.g., colchicine; (xi) xanthine oxidase inhibitors,e.g., allopurinol; (xii) uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone; (xiii) growth hormone secretagogues;(xiv) transforming growth factor (TGFβ); (xv) platelet-derived growthfactor (PDGF); (xvi) fibroblast growth factor, e.g., basic fibroblastgrowth factor (bFGF); (xvii) granulocyte macrophage colony stimulatingfactor (GM-CSF); (xviii) capsaicin cream; (xix) Tachykinin NK₁ and NK₃receptor antagonists selected from the group consisting of NKP-608C;SB-233412 (talnetant); and D-4418; (xx) elastase inhibitors selectedfrom the group consisting of UT-77 and ZD-0892; (xxi) TNFα convertingenzyme inhibitors (TACE); (xxii) induced nitric oxide synthaseinhibitors (iNOS) or (xxiii) chemoattractant receptor-homologousmolecule expressed on TH2 cells.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, droloxifene, lasofoxifeneor fosomax and immunosuppressant agents such as FK-506, rapamycin,cyclosporine, azathioprine, and methotrexate;

The compounds of the invention may also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib,valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticulartherapies such as corticosteroids and hyaluronic acids such as hyalganand synvisc and P2X7 receptor antagonists.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of cancer. Suitable agentsto be used in combination include:

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine and paclitaxel (Taxol®); antitumour antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere); and topoisomerase inhibitors (for example epipodophyllotoxinslike etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) Agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in International Patent ApplicationsWO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compoundsthat work by other mechanisms (for example linomide, inhibitors ofintegrin αvβ3 function and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO99/02166, WO00/40529,WO00/41669, WO01/92224, WO02/04434 and WO02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

In a still further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for the treatment of human diseases or conditions in whichmodulation of CRTh2 receptor activity is beneficial.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention still further provides a method of treating diseasesmediated by PGD2 or its metabolites wherein the prostanoid binds to itsreceptor (especially CRTh2) receptor, which comprises administering to apatient a therapeutically effective amount of a compound of formula (I),or a pharmaceutically acceptable salt, solvate or prodrug thereof, ashereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially psoriasis, in a patient suffering from, or at riskof, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compound of formula (I), prodrugs and pharmaceutically acceptablesalts and solvates thereof may be used on their own but will generallybe administered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as herein before defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as herein before defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) the title and sub-titled compounds of the examples and methods werenamed using the ACD labs/name program (version 6.0) from AdvancedChemical Development Inc, Canada;(ii) unless stated otherwise, reverse phase preparative HPLC wasconducted using a Symmetry, NovaPak or Ex-Terra reverse phase silicacolumn;(iii) Flash column chromatography refers to normal phase silicachromatography(iv) solvents were dried with MgSO₄ or Na₂SO₄(v) Evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;(vi) Unless otherwise stated, operations were carried out at ambienttemperature, that is in the range 18-25° C. and under an atmosphere ofan inert gas such as argon or nitrogen;(vii) yields are given for illustration only and are not necessarily themaximum attainable;(viii) the structures of the end-products of the formula (I) wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;(ix) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), mass spectrometry (MS), infra-red (IR) or NMRanalysis;(x) mass spectra (MS): generally only ions which indicate the parentmass are reported when given, ¹H NMR data is quoted in the form of deltavalues for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMS) as an internal standard;(xi) the following abbreviations are used:M.p.=melting pointTHF=tetrahydrofuranEtOAc=ethyl acetateMCPBA=meta chloroperbenzoic acidAMY=N,N-dimethyl formamideMgSO₄=magnesium sulfateNa₂SO₄=sodium sulfateNaHCO₃=sodium hydrogen carbonate

EXAMPLE 1

4-(Acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid i) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole

To a stirred solution of 3-nitroaniline (8 g) in THF (700 ml) cooled to−78° C. was added tert-butyl hypochlorite (6.3 g) dropwise over 5minutes. The reaction was allowed to warm to −65° C. over 20 minutesbefore 1-[4-chlorophenyl)thio]-2-propanone (11.6 g) was added as asolution in THF (20 ml). After 2 hours triethylamine (8.1 ml) was addedand the reaction allowed to warm to room temperature. 2M HCl (aq) wasadded to the reaction mixture before concentration in vacuo. The residuewas slurried in methanol and the solid which precipitated isolated byfiltration to give the sub-title compound (5.8 g).

¹H NMR (DMSO-d6) δ 12.55 (s, 1H), 7.76 (dd, 1H), 7.63 (dd, 1H),7.31-7.22 (m, 3H), 6.91 (dd, 2H), 2.47 (s, 3H)

ii) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-acetic acid,ethyl ester

To a stirred suspension of sodium hydride, 60% dispersion in mineraloil, (0.85 g) in THF (100 ml) was added the product from part (i) (5.6g) as a solution in THF (50 ml). After stirring at room temperature for30 minutes ethyl bromoacetate (2.3 ml) was added dropwise over 10minutes. After 2 hours the reaction was concentrated in vacuo, theresidue dissolved in ethyl acetate, washed with water, brine, dried(MgSO₄) and concentrated in vacuo. Recrystallisation from ethanol gavethe sub-title compound (5 g).

¹H NMR (DMSO-d6) δ 7.97 (dd, 1H), 7.65 (dd, 1H), 7.35 (t, 1H), 7.26 (dt,2H), 6.92 (dt, 2H), 5.40 (s, 2H), 4.19 (q, 2H), 2.45 (s, 3H), 1.22 (t,3H).

iii) 4-amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-acetic acid,ethyl ester

A suspension of the product from part (ii) (2.25 g) in ethanol (170 ml)was stirred in the presence of 5% Pt/C (0.5 g) under 2 bar pressure ofH₂. After stirring overnight the catalyst was removed by filtration andthe filtrates concentrated in vacuo. Purification by flash columnchromatography (14% EtOAc/hexane as eluent) to give the sub-titlecompound (1.4 g).

¹H NMR (DMSO-d6) δ 7.30 (dd, 2H), 7.00 (dt, 2H), 6.85 (t, 1H), 6.68 (dd,1H), 6.23 (dd, 1H), 5.33 (s, 2H), 5.09 (s, 2H), 4.16 (q, 2H), 2.33 (s,3H), 1.21 (t, 3H).

3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-aceticacid, ethyl ester was also isolated as a by product from the reaction(0.33 g).

¹H NMR (DMSO-d6) δ 7.32 (dd, 2H), 7.01 (dd, 2H), 6.95 (t, 1H), 6.73 (d,1H), 6.16 (d, 1H), 5.70 (t, 1H), 5.11 (s, 2H), 4.16 (q, 2H), 3.05 (dt,2H), 2.34 (s, 3H), 1.21 (t, 3H), 1.02 (t, 3H).

iv) 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-aceticacid, ethyl ester

To a solution of the product from part (iii) (0.5 g) in dichloromethane(10 ml) was added triethylamine (0.18 ml) and acetyl chloride (0.1 ml),the reaction was stirred at room temperature for 30 minutes. The mixturewas then adsorbed onto silica gel and purified by column chromatography(33% EtOAc/hexane as eluent) to give the sub-title compound (0.52 g).

¹H NMR (DMSO-d6) δ 9.51 (s, 1H), 7.46 (d, 1H), 7.34-7.27 (m, 3H), 7.11(t, 1H), 6.97 (d, 2H), 5.24 (s, 2H), 4.18 (q, 2H), 2.39 (s, 3H), 1.86(s, 3H), 1.21 (t, 3H).

v) 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-aceticacid

To a solution of the product from part (iv) (0.31 g) in THF (10 ml) wasadded a 1M solution of NaOH (aq) (0.75 ml). The reaction was stirredovernight at room temperature. The reaction mixture was concentrated invacuo and the residue dissolved/suspended in water. The pH was adjustedto 2 using dilute HCl (aq) and the solid which precipitated isolated byfiltration. Recrystallisation from acetonitrile gave the title compound(0.16 g).

¹H NMR (DMSO-d6) δ 13.21 (s, 1H), 9.51 (s, 1H), 7.46 (d, 1H), 7.33-7.27(m, 3H), 7.11 (t, 1H), 6.98 (d, 2H), 5.12 (s, 2H), 2.39 (s, 3H), 1.85(s, 3H).

APCI+ [M+H] 389

M.p. dec>266° C.

EXAMPLE 2

3-[(4-Chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

To a solution of the product from Example 1 part (iii) (0.5 g) indichloromethane (10 ml) were added triethylamine (0.18 ml) and methanesulfonyl chloride (0.1 ml), and the reaction was stirred at roomtemperature for 2 hours before heating at reflux overnight. Thedichloromethane was removed in vacuo, acetonitrile added (10 ml) and thereaction was heated to 60° C. for 5 hours. The mixture was adsorbed ontosilica gel and purified by column chromatography (33% EtOAc/hexane aseluent) to give the sub-title compound (0.44 g).

¹H NMR (DMSO-d6) δ 8.80 (s, 1H), 7.39 (d, 1H), 7.32 (d, 2H), 7.20-7.07(m, 2H), 6.97 (d, 2H), 5.27 (s, 2H), 4.18 (q, 2H), 2.74 (s, 3H), 2.38(s, 3H), 1.22 (t, 3H).

ii)3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v),using the product from part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 8.80 (s, 1H), 7.39 (d, 1H), 7.32 (m,2H), 7.16 (t, 1H), 7.09 (d, 1H), 6.98 (dt, 2H), 5.15 (s, 2H), 2.73 (s,3H), 2.38 (s, 3H).

APCI− [M−H] 423

M.p. dec>243° C.

EXAMPLE 3

3-[(4-Chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-aceticacid

i) 4-bromo-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole

3-bromophenyl hydrazine hydrochloride (15.34 g) in water (80 ml) wasadded to a suspension of 1-[(4-chlorophenyl)thio]acetone (13.77 g) inacetonitrile (200 ml) and stirred overnight at room temperature and thenconcentrated in vacuo. The residue was partitioned between aqueoussodium hydrogen carbonate and dichloromethane. The organic phase waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The residualoil was treated with acetic acid (70 ml) and heated at 80° C. overnight.The reaction mixture was poured into water, basified with aqueous sodiumhydroxide and extracted with EtOAc (twice). The combined organics werewashed (brine), dried (MgSO₄) and concentrated in vacuo.

The mixture was purified by flash column chromatography (40%EtOAc/hexane as eluent) to give the sub-title compound (4.43 g).

¹H NMR (DMSO-d6) δ 7.31 (s, 1H), 7.30 (d, 2H), 7.13 (dt, 2H), 7.02 (t,1H), 6.94 (dt, 2H), 2.52 (s, 3H).

ii) 4-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1-1H-indole-1-acetic acid,1,1-dimethylethyl ester

The sub-title compound was prepared by the method of Example 1 part (ii)using the product of part (i) and t-butyl bromoacetate. The product waspurified using column chromatography (10% EtOAc/hexane as eluent).

¹H NMR (CDCl₃: δ 7.31 (dd, 1H), 7.21 (dd, 1H), 7.14-7.10 (m, 2H), 7.05(t, 1H), 6.94-6.91 (m, 2H), 4.77 (s, 2H), 2.49 (s, 3H), 1.43 (s, 9H).

iii)3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-aceticacid, 1,1-dimethylethyl ester

To a solution/suspension of the product of part (ii) (500 mg) in toluene(4 ml) was added ethanol (1 ml), 5-pyrimidinyl-boronic acid (133 mg), 2Msodium carbonate (1.5 ml) and finallytetrakis(triphenylphosphine)palladium (0), (125 mg). The mixture washeated at 100° C. for 3 days. Purification by column chromatography(eluent 2:1 Hexane:EtOAc) gave the sub-title compound as an orange solid(140 mg).

¹H NMR (DMSO-d6) δ 8.99 (s, 1H), 8.57 (s, 2H), 7.68 (d, 1H), 7.10 (dd,2H), 6.99 (d, 1H), 7.30 (dt, 1H), 6.46 (dd, 2H), 5.21 (s, 2H), 2.42 (s,3H), 1.45 (s, 9H).

iii)3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from step (iii), with purification by reverse phasehplc (MeCN/NH₃(aq) as eluent).

¹H NMR (DMSO-d6) δ 8.99 (s, 1H), 8.57 (s, 2H), 7.69 (d, 1H), 7.29 (t,1H), 7.10 (m, 2H), 6.98 (d, 1H), 6.47 (m, 2H), 5.19 (s, 2H), 2.43 (s,3H). APCI-[M−H] 408

EXAMPLE 4

3-[(4-Chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic acid i)3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic acid,1,1-dimethylethyl ester

To a solution of the product from Example 3 part (ii) (0.4 g) in toluene(4 ml) was added 2-tributylstannylpyrazine (0.32 g) andtetrakis(triphenylphosphine)palladium (0) (0.1 g). The reaction mixturewas heated to 80° C. for 18 hours. The mixture was adsorbed onto silicaand purified using column chromatography (33% EtOAc/hexane as eluent) togive the sub-title compound (160 mg).

¹H NMR (DMSO-d6) δ 8.52 (d, 1H), 8.47 (d, 1H), 8.41 (t, 1H), 7.68 (d,1H), 7.30 (t, 1H), 7.13-7.09 (m, 3H), 6.55 (m, 2H), 5.21 (s, 2H), 2.40(s, 3H), 1.44 (s, 9H).

ii) 3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v),with purification by preparative hplc (MeCN/NH₃(aq) as eluent).

¹H NMR (DMSO-d6) δ 8.50 (d, 1H), 8.45 (d, 1H), 8.41 (dd, 1H), 7.56 (dd,1H), 7.22 (dd, 1H), 7.13-7.09 (m, 2H), 7.04 (dd, 1H), 6.58 (dt, 2H),4.68 (s, 2H), 2.38 (s, 3H) APCI− [M−H] 408

EXAMPLE 5

3-[(2-Chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i) 2-methyl-5-nitro-1H-indole-1-acetic acid, ethyl ester

2-Methyl-5-nitro-1H-indole (5.3 g) was dissolved in dimethyl formamide(20 ml) and to it added sodium hydride (1.2 g) for the mixture to bestirred for 1 hour. Ethyl bromoacetate (6.8 g) was added all at once anda precipitate started to form. The mixture was quenched with 1% aqueousacetic acid and the precipitate collected by filtration and washedthoroughly with water, triturated with diethyl ether and dried undervacuum to give pure sub-title product (6.2 g).

¹H NMR (DMSO-d6) δ 8.45 (d, 1H), 7.96 (dd, 1H), 7.59 (d, 1H), 6.56 (s,1H), 5.21 (s, 2H), 4.16 (q, 2H), 2.37 (s, 3H), 1.19 (t, 3H).

APCI− [M−H] 263

ii) 5-amino-2-methyl-1H-indole-1-acetic acid, ethyl ester

A suspension of 2-methyl-5-nitro-1H-indole-1-acetic acid, ethyl ester(6.2 g) in ethanol (600 ml) in the presence of 10% palladium on charcoal(0.6 g) was stirred under a hydrogen atmosphere at 3 bar for 4 hours.The mixture was filtered through celite and the filtrate evaporated togive the sub-title compound as a pink viscous oil (5.3 g). APCI− [M−H]233

iii) 2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid, ethylester

Methanesulfonyl chloride (1.15 g) was added to a solution of5-amino-2-methyl-1H-indole-1-acetic acid, ethyl ester (2.3 g) intriethylamine (1.7 ml) and dichloromethane (20 ml) at 0° C. a pinkviscous oil for a pink viscous oil for and stirred at 20° C. for 1 hour.Water was added and the mixture extracted with dichloromethane, dried(Na₂SO₄) and evaporated to give the crude solid. This was purified bychromatography using silica (40:1 dichloromethane/ethyl acetate aseluent) to give the sub-title compound as a pink solid (1.4 g).

¹H NMR (DMSO-d6) δ 9.23 (s, 1H), 7.30 (m, 2H), 6.94 (dd, 1H), 6.23 (s,1H), 5.03 (s, 2H), 4.14 (q, 2H), 2.85 (s, 3H), 2.31 (s, 3H), 1.19 (t,3H). APCI− [M−H] 311

iv)3-[(2-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid, ethyl ester(0.31 g) and 2-chlorobenzenethiol (0.27 g) were dissolved in dimethylformamide (3 ml) followed by addition of iodine 0.30 g) for the whole tobe stirred at room temperature overnight. The mixture was poured intoaqueous sodium thiosulphate (50 ml) and the resultant white precipitatecollected by filtration and rinsed with water, dried under vacuum to berecrystallised from ethanol. The crystals were harvested and rinsed withisohexane and dried under vacuum to give the sub-title compound (0.20 g)

¹H NMR (DMSO-d6) δ 9.34 (s, 1H), 7.55 (d, 1H), 7.45 (m, H), 7.21 (d,1H), 7.23-7.06 (m, 311), 6.44 (m, 1H), 5.26 (s, 2H), 4.18 (q, 2H), 2.83(s, 3H), 2.38 (s, 3H), 1.22 (t, 3H). APCI− [M−H] 453/455

v)3-[(2-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)except that recrystallisation was not required. (0.10 g)

¹H NMR (DMSO-d6) δ13.25 (s, 1H), 9.33 (s, 1H), 7.54 (d, 1H), 7.45 (dd,1H), 7.21 (d, 1H), 7.08 (m, 3H), 6.45 (d, 1H), 5.13 (s, 2H), 2.83 (s,3H), 2.38 (s, 3H). APCI− [M−H] 425/427

M.p. 212° C.

EXAMPLE 6

3-[(3-Chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid i)3-[(3-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product of Example 5 part (iv) and 3-chlorobenzenethiol (0.34g).

APCI− [M−H] 453/455

ii)3-[(3-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 part (v)using the product from Example 6 part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.33 (s, 1H), 7.46 (d, 1H), 7.21 (m,2H), 7.11 (dd, 1H), 7.07 (dd, 1H), 6.95 (m, 2H), 4.88 (s, 2H), 2.82 (s,3H), 2.39 (s, 3H).

APCI+ [M+H] 425/427

M.pt. 224° C.

EXAMPLE 7

3-[(4-Chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product of Example 5 part (iv) and 4-chlorobenzenethiol.

APCI− [M−H] 453/455

ii)3-[(4-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 part (v)using the product from part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.37 (s, 1H), 7.57 (d, 1H), 7.23 (d,2H), 7.22 (d, 1H), 7.07 (dd, 1H), 6.96 (d, 2H), 5.11 (s, 2H), 2.82 (s,3H), 2.39 (s, 3H).

APCI+ [M+H] 425/427

M.p. 214° C.

EXAMPLE 8

3-[(3-Methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i)3-[(3-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product of Example 5 part (iv) and 3-methoxybenzenethiol APCI−[M−H] 449

ii)3-[(3-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 part (v)using the product from part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.34 (s, 1H), 7.50 (d, 1H), 7.26, d,1H, 7.08 (t, 1H), 7.06 (dd, 1H), 6.64 (dd, 1H), 6.55 (d, 1H), 6.47 (d,1H), 5.11 (s, 2H), 3.62 (s, 3H), 2.82 (s, 3H), 2.40 (s, 3H).

APCI− [M−H] 421

M.p. 292° C.

EXAMPLE 9

3-[(4-Methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i)3-[(4-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product of Example 5 part (iv) and 4-methoxybenzenethiol.

APCI− [M−H] 449

ii)3-[(4-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 part (v)using the product from part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.33 (s, 1H), 7.46 (d, 1H), 7.03 (d,1H), 7.04 (dd, 1H), 7.00 (d, 2H), 6.81 (d, 2H), 5.07 (s, 2H), 3.67 (s,3H), 2.83 (s, 3H), 2.42 (s, 3H).

APCI+ [M+H] 421

M.p. 215° C.

EXAMPLE 10

3-[(2-Trifluoromethylphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i) 3-[(2-trifluoromethylphenyl)thio]-2-methyl-54(methylsulfonyl)amino]-1H-indole-1-acetic acid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product of Example 5 part (iv) and2-trifluoromethylbenzenethiol.

APCI− [M−H] 487

ii)[(2-trifluoromethylphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 part (v)using the product from part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.35 (s, 1H), 7.72 (d, 1H), 7.54 (d,1H), 7.36 (t, 7.24 (t, 1H), 7.22 (s, 1H), 7.11 (dd, 1H), 6.73 (d, 1H),5.12 (s, 2H), 2.82 (s, 3H), 2.40 (s, 3H).

APCI− [M−H] 459

M.p. 207° C.

EXAMPLE 11

3-[(8-Quinolinyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i)3-[(8-quinolinyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product of Example 5 part (iv) and 8-quinolinthiol.

APCI− [M−H] 470

ii)3-[(8-quinolinyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound prepared by the method of Example 5 part (v) usingthe product from part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.29 (s, 1H), 8.99 (dd, 1H), 8.38 (d,1H), 7.65 (m, 2H), 7.54 (d, 1H), 7.30 (t, 1H), 7.20 (s, 1H), 7.11 (dd,1H), 6.68 (d, 1H), 5.14 (s, 2H), 2.80 (s, 3H), 2.40 (s, 3H).

APCI+ [M+H] 442

M.p. 257° C.

EXAMPLE 12

3-[(2-(Methylethyl)phenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid i)3-[(2-(2-methylethyl)phenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product of Example 5 part (iv) and2-(2-methylethyl)benzenethiol.

APCI− [M−H] 461

ii)3-[(2-(2-methylethyl)phenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 part (v)using the product from part (i).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.33 (s, 1H), 7.49 (d, 1H), 7.27 (d,1H), 7.22 (d, 1H), 7.06 (m, 2H), 6.89 (t, 1H), 6.50 (dd, 1H), 5.10 (s,2H), 3.50 (m, 1H), 2.81 (s, 3H), 2.39 (s, 3H), 1.33 (s, 3H), 1.31 (s,3H).

APCI+ [M+H] 433

M.p. 160° C.

EXAMPLE 13

5-(Acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid i) 5-(acetylamino)-2-methyl-1H-indole-acetic acid, ethyl ester

Acetyl chloride (0.10 g) was added to a solution of the product fromExample 5 part ii) (0.28 g) in dichloromethane (10 ml) and triethylamine(0.2 ml) at 0° C. and left to stir at 20° C. for 1 hour. Water was addedand the mixture extracted with dichloromethane, dried (Na₂SO₄) andpurified by column chromatography (eluting with 1:1 iso-hexane/ethylacetate) to give the sub-title compound as a pink powder (0.19 g).

¹H NMR (DMSO-d6) δ 9.69 (s, 1H), 7.73 (d, 1H), 7.22 (d, 1H), 7.12 (dd,1H), 6.18 (s, 1H), 5.00 (s, 2H), 4.13 (q, 2H), 2.30 (s, 3H), 2.02 (s,3H), 1.20 (t, 3H).

APCI− [M−H] 275

ii) 5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from part (i) (0.19 g) and 4-chlorobenzenethiol (0.20g). The mixture was poured into aqueous sodium thiosulphate, extractedwith ethyl acetate, washed with water, dried (Na₂SO₄) and evaporated.The residue was recrystallised from ethanol to give the sub-titlecompound as a pink solid (0.13 g).

¹H NMR (DMSO-d6) δ 9.80 (s, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.36 (dd,1H), 7.27 (d, 2H), 6.94 (d, 2H), 5.20 (s, 2H), 4.16 (q, 2H), 2.39 (s,3H), 1.98 (s, 3H), 1.21 (t, 3H).

APCI− [M−H] 417/419

iii) 5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-aceticacid

The title compound was prepared by the method of Example 5 part (v)using the product from part (ii).

¹H NMR (DMSO-d6) δ 13.25 (s, 1H), 9.79 (s, 1H), 7.67 (d, 1H), 7.42 (d,1H), 7.34 (dd, 1H), 7.27 (d, 2H), 6.96 (d, 2H), 5.07 (s, 2H), 2.39 (s,3H), 1.98 (s, 3H).

APCI+ [M+H] 389/391

M.p. 247° C.

EXAMPLE 14

4-(Acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 1 part (iv)using the by-product from Example 1 part (iii).

¹H NMR (DMSO-d6) δ 7.53 (d, 1H), 7.22-7.18 (m, 3H), 6.91-6.87 (m, 3H),5.21 (s, 2H), 4.19 (q, 2H), 4.01 (m, 1H), 2.92-2.81 (m, 1H), 2.41 (s,3H), 1.31 (s, 3H), 1.21 (t, 3H), 0.91 (t, 3H)

ii)4-(acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v) andthe product from part (i).

¹H NMR (DMSO-d6) δ 7.55 (d, 1H), 7.22 (dt, 2H), 7.18 (t, 1H), 6.89-6.86(m, 3H), 4.99 (s, 2H), 2.77 (m, 1H), 4.02 (m, 1H), 2.39 (s, 3H), 1.28(s, 3H), 0.91 (t, 3H).

APCI+ [M+H] 417 EXAMPLE 15

3-[(4-Chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 1 part (iv)using the product from Example 1 part (iii) and cyclopropylcarbonylchloride.

¹H NMR (DMSO-d6) δ 9.74 (s, 1H), 7.49 (d, 1H), 7.43-7.26 (m, 3H), 7.10(t, 1H), 6.98 (m, 2H), 5.24 (s, 2H), 4.18 (q, 2H), 2.40 (s, 3H), 1.53(m, 1H), 1.18 (t, 3H), 0.64 (m, 4H).

ii)3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-1-aceticacid

The sub-title compound was prepared using the method of Example 1 part(v) and the product from part (i).

¹H NMR (DMSO-d6) δ 9.58 (s, 1H), 7.60 (d, 1H), 7.28-7.22 (m, 3H), 7.09(t, 1H), 7.02 (m, 2H), 5.03 (s, 2H), 2.41 (s, 3H), 1.50 (m, 1H), 0.68(m, 4H)

APCI− [M−H] 413

M.p. 183-185° C.

EXAMPLE 16

4-(Benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid i)4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 1 part (iv)using the product from Example 1 part (iii) and benzoyl chloride.

¹H NMR (DMSO-d6) δ 10.25 (s, 1H), 7.84 (d, 1H), 7.75 (m, 2H), 7.59 (m,1H), 7.50 (m, 2H), 7.40 (d, 1H), 7.21 (m, 3H), 6.88 (m, 2H), 5.28 (s,2H), 4.19 (q, 2H), 2.40 (s, 3H), 1.17 (t, 3H).

ii)4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared using the method of Example 1 part (v)and the product from part (i).

¹H NMR (DMSO-d6) δ 10.26 (s, 1H), 7.86 (d, 1H), 7.75 (dt, 2H), 7.58 (m,1H), 7.50 (m, 2H), 7.36 (dd, 1H), 7.21 (dt, 2H), 7.17 (t, 1H), 6.90 (dt,2H), 5.03 (s, 2H), 2.40 (s, 3H).

APCI− [M−H] 449

M.pt 213-215° C.

EXAMPLE 17

4-(Acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid i) 4-(acetylamino)-2-methyl-1H-indole-1-acetic acid, ethyl ester

Thiosalicylic acid was added to a solution of the product from Example 1part (iv) (474 mg) in trifluoroacetic acid (10 ml) was addedthiosalicylic acid (351 mg) and the resulting suspension was heated to60° C. for 4 hours. The mixture was concentrated in vacuo and theresidue dissolved in EtOAc and washed with NaHCO₃ (aq), brine, dried(MgSO₄) and evaporated to give crude material. Purification by columnchromatography (50% EtOAc/hexane as eluent) gave the sub-title compound(0.13 g).

¹H NMR (DMSO-d6) δ 9.51 (s, 1H), 7.54 (d, 1H), 7.07 (d, 1H), 6.96 (t,1H), 6.50 (s, 1H), 5.02 (s, 2H), 4.14 (q, 2H), 2.33 (d, 3H), 2.12 (s,3H), 1.20 (t, 3H).

ii) 4-(acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from part (i) (0.11 g) and 3-chlorobenzenethiol (0.048g), then purified by preparative hplc (eluent MeCN/NH₃(aq)) to give thetitle compound (70 mg).

¹H NMR (DMSO-d6) δ 9.49 (s, 1H), 7.43 (d, 1H), 7.29 (d, 1H), 7.24 (t,1H), 7.14 (dd, 1H), 7.08 (t, 1H), 6.97-6.95 (m, 2H), 4.96 (s, 2H), 2.38(s, 3H), 1.86 (s, 3H).

APCI− [M−H] 387

EXAMPLE 18

3-[(4-Chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-indole-1-aceticacid, ethyl ester

Triethylamine (55 μl) and dimethylsulfamoyl chloride (43 μl) were addedto a solution of the product from Example 1 part (iv) (150 mg) inacetonitrile (5 ml). The mixture was heated at reflux for 24 hours,adsorbed onto silica and purified using column chromatography (33%EtOAc/hexane as eluent) to give the sub-title compound (95 mg).

¹H NMR (DMSO-d6) δ 8.80 (s, 1H), 7.35-7.29 (m, 3H), 7.13 (t, 1H), 7.07(dd, 1H), 6.99 (dt, 2H), 5.25 (s, 2H), 4.18 (q, 2H), 2.56 (s, 6H), 2.37(s, 3H), 1.21 (t, 3H).

ii)3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared using the method of Example 1 part (v)and the product from part (i).

¹H NMR (DMSO-d6) δ 8.79 (s, 1H), 7.31 (m, 2H), 7.14 (dd, 1H), 7.04-6.99(m, 4H), 4.51 (s, 2H), 2.54 (s, 6H), 2.34 (s, 3H).

APCI− [M−H] 452

EXAMPLE 19

3-[(4-Chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]-1H-indole-1-aceticacid, ethyl ester

Triethylamine (75 μl) and 1-methyl-1H-imidazole-4-sulfonyl chloride (96mg) were added to a solution of the product from Example 1 part (iii)(0.2 g) in acetonitrile (20 ml) and the mixture was heated at refluxovernight, cooled, adsorbed onto silica and purified using columnchromatography (70% EtOAc/hexane as eluent) to give the sub-titlecompound as an oil (245 mg).

¹H NMR (DMSO-d6) δ 9.17 (s, 1H), 7.73 (d, 1H), 7.63 (d, 1H), 7.32 (dt,2H), 7.24 (dd, 1H), 7.08-7.02 (m, 2H), 6.98 (dt, 2H), 5.20 (s, 2H), 4.15(q, 2H), 3.60 (s, 3H), 2.33 (s, 3H), 1.17 (t, 3H).

ii)3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]-1H-indole-1-aceticacid

The title compound was prepared using the method of Example 1 part (v)and the product from part (i).

¹H NMR (DMSO-d6) δ 9.16 (s, 1H), 7.73 (d, 1H), 7.62 (d, 1H), 7.31 (dt,2H), 7.22 (dd, 1H), 7.08-7.02 (m, 2H), 6.99 (dt, 2H), 5.01 (s, 2H), 3.59(s, 3H), 2.32 (s, 3H).

APCI− [M−H] 489

EXAMPLE 20

3-[(4-Chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 1 part (iv)using the product from Example 1 part (iii) and (dimethylamino)-acetylchloride, hydrochloride. The product was purified using columnchromatography (33% EtOAc/hexane as eluent).

¹H NMR (DMSO-d6) δ 10.77 (s, 1H), 8.15 (d, 1H), 7.35-7.27 (m, 3H), 7.13(t, 1H), 6.97 (d, 2H), 5.25 (s, 2H), 4.17 (q, 2H), 2.94 (s, 2H), 2.38(s, 3H), 2.10 (s, 6H), 1.21 (t, 3H).

ii)3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared using the method of Example 1 part (v)and the product from part (i).

¹H NMR (DMSO-d6) δ 10.76 (s, 1H), 8.10 (d, 1H), 7.30 (dt, 2H), 7.17 (d,1H), 7.05 (t, 1H), 6.98 (dd, 2H), 4.66 (s, 2H), 2.93 (s, 2H), 2.35 (s,3H), 2.09 (s, 6H).

APCI− [M−H] 430

EXAMPLE 21

4-(Acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid i) 4-(methylsulfonyl)benzenethiol

1-fluoro-4-(methylsulfonyl)benzene and sodium bisulphide (10 g) wereheated in NMP (10 ml) at 80° C. for 2 h. The mixture was poured intowater, washed with EtOAc, acidified with, concentrated hydrochloric acidand extracted with EtOAc. The organics were washed with water, dried(MgSO₄) and evaporated to give the sub-title compound, which was used inthe next step without characterisation.

ii)4-(acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from part (i) and the product from Example 17 part(i), and purified by chromatography (50% EtOAc/hexane increasing to 66%EtOAc/hexane as eluent) to give the sub-title compound.

¹H NMR (DMSO-d6) δ 9.45 (s, 1H), 7.72 (dt, 2H), 7.38 (d, 1H), 7.32 (d,1H), 7.16-7.11 (m, 3H), 5.27 (s, 2H), 4.19 (q, 2H), 3.14 (s, 3H), 2.38(s, 3H), 1.82 (s, 3H), 1.22 (t, 3H).

iv)4-(acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

The title compound was prepared using the method of Example 1 part (v)and the product from part (ii).

¹H NMR (DMSO-d6) δ 9.44 (s, 1H), 7.72 (dd, 2H), 7.38 (d, 1H), 7.31 (d,1H), 7.17-7.10 (m, 3H), 5.14 (s, 2H), 3.14 (s, H), 2.38 (s, 3H), 1.82(s, 3H).

APCI− [M−H] 431

EXAMPLE 22

4-(Acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid4-(acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 parts (iv)and using the product from Example 17 part (i) and 2-chlorothiophenol,and purified by column chromatography (33% EtOAc/hexane as eluent). Theresulting product was treated as outlined in example 1 part (v) to givethe title compound.

¹H NMR (DMSO-d6) δ 9.43 (s, 1H), 7.46 (dd, 1H), 7.37 (dd, 2H), 7.14-7.05(m, 3H), 6.42 (dd, 1H), 5.14 (s, 2H), 2.37 (s, 3H), 1.81 (s, 3H)

APCI+ [M+H] 389

EXAMPLE 23

4-(Acetylamino)-2-methyl-3-[[4-(ethylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid i)4-(acetylamino)-2-methyl-3-[[4-(ethylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 5 part (iv)using the product from Example 17 part (i) and4-(ethylsulfonyl)benzenethiol. The product was purified by preparativehplc (eluent MeCN/NH₃(aq)).

¹H NMR (DMSO-d6) δ 9.41 (s, 1H), 7.66 (d, 2H), 7.30 (d, 2H), 7.17 (d,2H), 7.08 (t, 1H), 4.85 (s, 2H), 3.20 (q, 2H), 2.37 (s, 3H), 1.78 (s,3H), 1.05 (t, 3H).

APCI− [M−H] 445

EXAMPLE 24

3-[(4-Chlorophenyl)thio]-4-[[(ethylamino)carbonyl]amino]-2-methyl-1H-indole-1-aceticacid i)3-[(4-chlorophenyl)thio]-4-[[(ethylamino)carbonyl]amino]-2-methyl-1H-indole-1-aceticacid, ethyl ester

Ethyl isocyanate (32 μl) was added to a solution of the product fromExample 1 part (iii) (150 mg) in dichloromethane (10 ml). The reactionwas stirred at room temperature for 4 days before heating at reflux for24 hours. The mixture was adsorbed onto silica and purified using columnchromotography (33% EtOAc/hexane increasing to 50% EtOAc/hexane aseluent) to give sub-title compound (150 mg).

¹H NMR (DMSO-d6) δ 8.37 (s, 1H), 7.57 (d, 1H), 7.28 (dt, 2H), 7.12 (dd,1H), 7.06-6.98 (m, 3H), 6.81 (t, 1H), 5.19 (s, 2H), 4.17 (q, 2H), 2.98(dt, 2H), 2.37 (s, 3H), 1.21 (t, 3H), 0.96 (t, 3H)

ii)3-[(4-chlorophenyl)thio]-4-[[(ethylamino)carbonyl]amino]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared using the method of Example 1 part (v)and the product from part (i).

¹H NMR (DMSO-d6) δ 8.39 (s, 1H), 7.53 (dd, 1H), 7.26 (dt, 2H), 7.04-6.94(m, 4H), 6.76 (t, 1H), 4.56 (s, 2H), 2.98 (dt, 2H), 2.34 (s, 3H), 0.95(t, 3H).

APCI+ [M+H] 418

EXAMPLE 25

3-[[4-(Methylsulfonyl)phenyl]thio]-4-(5-pyrimidinyl)-1H-indole-1-aceticacid i) 4-bromo-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from Example 21 part (i) (0.89 g) and 4-bromoindole(0.96 g). The residue was purified by chromatography (50% EtOAc/hexaneas eluent) to give the sub-title compound (1.3 g).

¹H NMR (DMSO-d6) δ 12.18 (s, 1H), 7.93 (s, 1H), 7.73 (d, 2H), 7.56 (d,1H), 7.29 (d, 1H), 7.17 (d, 2H), 7.12 (t, 1H), 3.14 (s, 3H)

ii) 4-bromo-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic acid

Sodium t-butoxide (1.37 g) was added to a solution of the product frompart (i) (2.4 g) in DMF (20 ml) and the mixture stirred for 15 minutes.Ethyl bromoacetate (0.86 ml) was added and the mixture stirred for afurther 30 minutes. 1M sodium hydroxide (10 ml) was then added and themixture stirred for 2 hours. The mixture was diluted with water (200ml), washed with EtOAc (50 ml), acidified with 2M hydrochloric acid andthe resulting solid filtered off and dried to give the sub-titledcompound (2.5 g).

¹H NMR (DMSO-d6) δ 7.86 (s, 1H), 7.73 (d, 2H), 7.50 (d, 1H), 7.28 (d,1H), 7.19 (d, 2H), 7.11 (t, 1H), 4.73 (s, 2H), 3.14 (s, 3H)

iii)3-[[4-(methylsulfonyl)phenyl]thio]-4-(5-pyrimidinyl)-1H-indole-1-aceticacid

The product from part (ii) (0.4 g), phenylboronic acid (0.17 g),tetrakis(triphenylphosphine) palladium (100 mg) and 2M aqueous sodiumhydrogen carbonate (2 ml) were dissolved in ethanol (10 ml) and heatedat reflux for 8 hours. The mixture was cooled to room temperature,diluted with EtOAc (100 ml), washed with water and brine. The organicsolution was dried (MgSO₄), filtered and evaporated in vacuo and theresidue purified by hplc to give the title compound (190 mg).

¹H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.58 (s, 1H), 7.93 (s, 1H), 7.70 (d,1H), 7.52 (d, 2H), 7.37 (t, 1H), 7.03 (d, 1H), 6.70 (d, 2H), 5.15 (s,2H), 3.12 (s, 3H)

APCI− [M−H] 438

EXAMPLE 26

2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indole-1-aceticacid i) 1-[[4-(methylsulfonyl)phenyl]thio]acetone

The product from Example 21 part (i) (3.4 g) was dissolved in acetone(100 ml), potassium carbonate (3.0 g) added, followed by the dropwiseaddition of chloroacetone (1.5 ml). The mixture was stirred at roomtemperature for 20 hours, concentrated, partitioned between EtOAc andwater, dried (MgSO₄) and evaporated. The residue was purified bychromatography (50% EtOAc/hexane as eluent) to give the sub-titlecompound (2.6 g).

¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, 2H), 7.43 (d, 2H), 3.81 (s, 2H), 3.06(s, 3H), 2.34 (s, 3H)

APCI− [M−H] 243

M.p. 95-7° C.

ii) 4-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole

The sub-title compound was prepared by the method of Example 3 part (i)using the product from part (i) (1.6 g) and 3-bromophenyl hydrazinehydrochloride (1.47 g). The product was purified by using chromatography(30% EtOAc/hexane as eluent) to give the sub-title compound (0.5 g).

¹H NMR (CDCl₃) δ 8.41 (s, 1H), 7.68 (d, 2H), 7.54 (s, 1H), 7.32 (d, 1H),7.25 (d, 1H), 7.10 (d, 2H), 3.00 (s, 3H), 2.50 (s, 3H)

APCI− [M−H] 394

iii)4-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, 1,1-dimethylethyl ester

The sub-title compound was prepared by the method of Example 1 part (ii)using the product of part (i) and t-butylbromoacetate. The product waspurified using chromatography (50% EtOAc/hexane as eluent) to give thesub-title compound (0.5 g).

APCI+ [M+H] 510

iv)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indole-1-aceticacid, 1,1-dimethylethyl ester

A mixture of palladium acetate (24 mg), tri-ortho tolylphosphine (64 mg)and methanol (6 ml) were stirred under nitrogen for 10 minutes. Theproduct of part (ii) in methanol (10 ml) was added, followed by sodiumcarbonate (1.12 g) and thiophene-2-boronic acid (0.68 g). After stirringfor 45 minutes at 80° C. further palladium acetate (24 mg) and tri-orthotolylphosphine (64 mg) in methanol (1 ml) was added, followed bythiophene-2-boronic acid (0.2 g) and toluene (5 ml), the reactionmixture was stirred at 80° C. for 1 hour. The reaction mixture wasconcentrated in vacuo, water was added and the mixture extracted withdichloromethane. The organic layer was dried (MgSO₄) then concentratedin vacuo. The residue was dissolved in methanol and treated with sodiumhydroxide (5 ml). After one hour the reaction mixture was concentratedin vacuo, then purified by reverse phase HPLC to give the title compound(160 mg).

¹H NMR (DMSO-d6) δ 7.58 (m, 3H), 7.38 (d, 1H), 7.18 (t, 1H), 6.99 (d,1H), 6.87 (m, 3H), 6.78 (s, 1H), 4.98 (s, 2H), 3.11 (s, 3H), 2.38 (s,

APCI− [M−H] 456

EXAMPLE 27

4-(3,5-Dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

Prepared by the method of Example 26 part (iv) using the product ofExample 26 part (ii) and 3,5-dimethylisoxazolyl-4-boronic acid. Theproduct was purified using reverse phase preparative chromatography(eluent MeCN/NH₃(aq)) to give the title compound (6 mg).

¹H NMR (DMSO-d6) δ 7.61 (d, 1H), 7.46 (d, 2H), 7.17 (t, 1H), 6.82 (d,2H), 6.75 (d, 1H), 4.57 (s, 2H), 3.32 (s, 3H), 1.9 (s, 3H), 1.11 (s, 6H)

APCI− [M−H] 469

EXAMPLE 28

4-(3-Furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid i)4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 26 part(iv) using the product of Example 27 part (i) and furan-3-boronic acid.The product was used without characterisation in part (ii).

ii)4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (i). The product was purified using hplc(eluent MeCN/NH₃(aq)) to give the title compound (60 mg).

¹H NMR (DMSO-d6) δ 7.41-7.63 (m, 5H), 7.17 (t, 1H), 6.9-6.96 (m, 3H),6.36 (s, 1H), 5.18 (s, 2H), 3.18 (s, 3H), 2.4 (s, 3H)

APCI− [M−H] 440

EXAMPLE 29

2-Methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid i) 2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid

Thiosalicylic acid (0.35 g) was added to a solution of the product fromExample 2 part (i) (0.47 g) in TFA (10 ml). The mixture was stirred atroom temperature for 1 hour and then heated at 60° C. for 4 hours. TheTFA was evaporated and the residue dissolved in EtOAc. The organics werewashed with aqueous sodium bicarbonate and brine, dried (MgSO₄) andevaporated. The residue was purified using chromatography (50%EtOAc/hexane as eluent) to give the sub-title compound (0.16 g).

¹H NMR (DMSO-d6) δ 9.4 (s, 1H), 7.19 (d, 1H), 6.95-7.04 (m, 2H), 6.53(d, 1H), 5.04 (s, 2H), 4.15 (q, 2H), 2.91 (s, 3H), 2.32 (d, 3H), 1.21(t, 3H)

ii)2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from part (i) and the product from Example 21 part(i).

¹H NMR (DMSO-d6) δ 8.76 (s, 1H), 7.74 (dd, 2H), 7.44 (d, 1H), 7.07-7.21(m, 4H), 5.29 (s, 2H), 4.19 (q, 2H), 3.14 (s, 3H), 2.76 (s, 3H), 2.36(s, 3H), 1.22 (t, 3H)

iii)2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (ii) and the recrystallised from ethanol togive the title compound as a pale pink solid (75 mg).

¹H NMR (DMSO-d6) δ 8.78 (s, 1H), 7.74 (d, 2H), 7.44 (d, 1H), 7.13-7.2(m, 3H), 7.08 (d, 1H) 5.15 (s, 2H), 3.14 (s, 3H), 2.76 (s, 3H), 2.36 (s,3H)

APCI+ [M+H] 469

EXAMPLE 30

2-Methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid i) O-[3-(methylsulfonyl)phenyl]carbamothioic acid, dimethyl ester

Sodium hydride (0.33 g) was added to a solution of3-(methylsulfonyl)phenol in DMF (10 ml) and stirred for 30 minutes.Dimethylcarbamothioic chloride (1.1 g) was added and the reaction heatedat 80° C. for 4 hours. The mixture was poured into aqueous ammoniumchloride, extracted with EtOAc, washed with water, dried (MgSO₄) andevaporated in vacuo. The residue was purified using chromatography(30-50% ether/hexane as eluent) to give the sub-title compound (1.3 g).

¹H NMR (DMSO-d6) δ 7.82 (dd, 1H), 7.69 (t, 1H), 7.59 (t, 1H), 7.39 (dd,1H), 3.47 (s, 3H), 3.37 (s, 3H), 3.08 (s, 3H)

APCI+ [M−H] 260

ii) S-[3-(methylsulfonyl)phenyl]carbamothioic acid, dimethyl ester

The product from part (i) (1.1 g) was dissolved in N,N-dimethylaniline(3 ml) and heated at 220° C. for 8 hours. The mixture was cooled, pouredinto 2M hydrochloric acid and extracted with EtOAc. The organics werewashed with 2M hydrochloric acid and water, dried (MgSO₄) and evaporatedin vacuo. The oily residue was treated with ether to give the sub-titlecompound as a white solid (0.9 g).

¹H NMR (DMSO-d6) δ 8.07 (d, 1H), 7.94 (dd, 1H), 7.79 (dd, 1H), 7.59 (t,1H), 3.04-3.12 (m, 6H), 3.07 (s, 3H)

APCI+ [M+H] 260

iii) 3-(methylsulfonyl)benzenethiol

The product from part (ii) (0.9 g) was suspended in 2M sodium hydroxide(70 ml) and heated at reflux for 1.5 h to give a brown solution. Thesolution was cooled, extracted with EtOAc, dried (MgSO₄) and evaporatedto give the sub-title compound (0.45 g).

¹H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.7 (m, 1H), 7.52 (m, 1H), 7.44 (t,1H), 3.67 (s, 1H), 3.06 (s, 3H)

APCI− [M−H] 187

iv)2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from part (iii) (0.22 g) and the product from Example5 part (iii) and recrystallised from ethanol.

¹H NMR (DMSO-d6) δ 7.58 (m, 2H), 7.34 (m, 2H), 7.18 (t, 2H), 6.28 (s,1H), 4.89 (s, 2H), 4.25 (q, 2H), 3.06 (s, 3H), 2.96 (s, 3H), 2.49 (s,3H), 1.28 (t, 3H)

APCI− [M+NH₄] 514

M.p. 176-8° C.

v)2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (iv). The basic solution was adjusted to pH5with 0.5M hydrochloric acid and the resulting precipitate filtered offand dried to give the title compound (0.19 g).

¹H NMR (DMSO-d6) δ 9.35 (s, 1H), 7.61 (m, 1H), 7.57 (d, 1H), 7.53 (d,1H), 7.46 (t, 1H), 7.24 (d, 1H), 7.18 (m, 1H), 7.08 (dd, 1H), 5.05 (s,2H), 3.17 (s, 3H), 2.82 (s, 3H), 2.41 (s, 3H)

APCI+ [M+NH₄] 469

M.p. 233-6° C.

EXAMPLE 31

2-Methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

i) 1-fluoro-2-(methylsulfonyl)benzene

A solution of oxone (17 g) in water (85 ml) was added to a solution of2-fluorothioanisole in acetonitrile (85 ml) and the mixture stirred atroom temperature for 20 hours. The mixture was concentrated, extractedwith EtOAc, washed with water, dried (MgSO₄) and evaporated to give thesub-title compound (5.9 g).

¹H NMR (DMSO-d6) δ 7.98 (t, 1H), 7.66 (m, 1H), 7.35 (t, 1H), 7.26 (t,1H), 3.23 (s, 3H)

ii) 2-(methylsulfonyl)benzenethiol

The sub-title compound was prepared by the method of Example 26 part (i)using the product from part (i) (5.4 g).

¹H NMR (DMSO-d6) 8.05 (d, 1H), 7.46 (m, 2H), 7.35 (m, 1H), 4.84 (s, 1H),3.21 (s, 3H)

APCI− [M−H] 187

iii)2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from part (ii) (1.3 g) and the product from Example 5part (iii) (0.6 g). The product was purified using chromatography(50-67% EtOAc/hexane as eluent) to give the sub-title compound (0.18 g).

¹H NMR (DMSO-d6) δ 8.05 (d, 1H), 7.16-7.27 (m, 4H), 6.77 (dd, 1H), 6.33(s, 1H), 4.9 (s, 2H), 4.26 (q, 2H), 3.44 (s, 3H), 2.88 (s, 3H), 2.5 (s,3H), 1.21 (t, 3H)

APCI− [M+NH₄] 514

M.p. 174-7° C.

v)2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

Prepared by the method of Example 1 part (v) using the product from part(iii). The basic solution was adjusted to pH5 with 0.5M hydrochloricacid and the resulting precipitate filtered and dried to give the titlecompound.

¹H NMR (DMSO-d6)

9.38 (s, 1H), 7.92 (dd, 114), 7.53 (d, 1H), 7.39 (m, 1H), 7.31 (m, 1H),7.16 (d, 1H), 7.10 (dd, 1H), 6.75 (dd, 1H), 5.11 (s, 2H), 3.51 (s, 3H),2.81 (s, 2.41 (s, 3H).

APCI+ [M+NH₄] 486

M.p. 227-30° C.

EXAMPLE 32

2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-aceticacid i) 5-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole

The sub-title compound was prepared by the method of Example 3 part (i)using the product from Example 26 part (i) (2.5 g) and 4-bromophenylhydrazine hydrochloride (2.3 g). The reaction mixture was evaporated tohalf volume and the resulting precipitate filtered off, washed withether and dried to yield the sub-title compound (2.2 g).

¹H NMR (DMSO-d6) δ 12.04 (s, 1H), 7.73 (d, 2H), 7.4 (m, 2H), 7.27 (dd,1H), 7.14 (d, 2H), 3.14 (s, 3H), 2.45 (s, 3H)

APCI− [M−H] 394

ii)5-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 1 part (ii)using the product of part (i) and the product was purified usingchromatography (33-50% EtOAc/hexane as eluent).

¹H NMR (DMSO-d6)

7.71 (d, 2H), 7.64 (d, 1H), 7.34 (dd, 1H), 7.16 (d, 1H), 7.1 (d, 2H),4.88 (s, 2H), 4.24 (q, 2H), 3.0 (s, 3H), 2.47 (s, 3H) 1.29 (t, 3H)

APCI+ [M+H] 482

iii)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 3 part(iii) using the product of part (ii) and pyrimidine-5-boronic acid.Carried forward to part (iii) without characterisation.

iv)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (iii). The basic solution was adjusted topH5 with 0.5M hydrochloric acid and the resulting precipitate filteredoff and dried to give the title compound (21 mg).

¹H NMR (DMSO-d6)

9.38 (s, 1H), 9.09 (s, 2H), 7.71-7.79 (m, 4H), 7.64 (dd, 1H), 7.17 (d,2H), 5.23 (s, 2H), 3.12 (s, 3H) 2.45 (s, 3H)

APCI+ [M+H] 454

M.p.>290° C.

EXAMPLE 33

2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(2-thiophenyl)-1H-indole-1-aceticacid i)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-thiophenyl)-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 3 part(iii) using the product of part (ii) and thiophene-2-boronic acid. Usedwithout further characterisation.

ii)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(2-thiophenyl)-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (ii). The basic solution was adjusted to pH5 with 0.5 M hydrochloric acid and the resulting precipitate filteredoff and dried, then recrystallised from acetonitrile to give the titlecompound.

¹H NMR (DMSO-d6)

7.72 (d, 2H), 7.63 (d, 1H), 7.53 (m, 2H), 7.42 (d, 1H), 7.39 (t, 1H),7.18 (d, 2H), 7.08 (m, 1H), 5.15 (s, 2H), 3.13 (s, 3H) 2.42 (s, 3H)

APCI− [M+H] 458

EXAMPLE 34

5-(3,5-Dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid i)5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 3 part(iii) using the product of part (ii) and3,5-dimethylisoxazolyl-4-boronic acid. Used in the next step withoutcharacterisation.

ii)5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (ii). The basic solution was adjusted to pH5with 0.5M hydrochloric acid and the resulting precipitate filtered,dried and recrystallised from cyclohexane/ethanol to give the titlecompound.

¹H NMR (DMSO-d6)

7.73 (d, 2H), 7.66 (d, 1H), 7.24 (d, 1H), 7.19 (m, 3H), 5.19 (s, 2H),3.13 (s, 3H) 2.44 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H)

APCI+ [M+H] 471

EXAMPLE 35

2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-aceticacid i)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 3 part(iii) using the product of part (ii) and pyridine-3-boronic acid.

¹H NMR (CDCl₃) δ 8.85 (s, 1H), 8.54 (s, 1H), 7.87 (m, 1H), 7.73-7.69 (m,3H), 7.49 (d, 1H), 7.39 (d, 1H), 7.33 (t, 1H), 7.14 (d, 2H), 4.95 (s,2H), 4.26 (q, 2H), 2.98 (s, 3H), 2.51 (s, 3H), 1.29 (t, 3H).

ii)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (ii). The basic solution was adjusted to pH5with 0.5M hydrochloric acid and the resulting precipitate filtered offand dried to give the title compound (20 mg).

¹H NMR (DMSO-d6)

8.84 (d, 1H), 8.5 (dd, 1H), 8.1 (m, 1H), 7.73-7.69 (d, 3H), 7.63 (d,1H), 7.53 (dd, 1H), 7.43 (dd, 1H), 7.18 (d, 2H), 5.22 (s, 2H), 3.12 (s,3H) 2.44 (s, 3H)

APCI+ [M+H] 453

EXAMPLE 36

2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indole-1-aceticacid i)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 3 part(iii) using the product of part (ii) and (1H-pyrazol-4-yl)-boronic acidand used in the next step without characterisation.

ii)2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (ii). The basic solution was adjusted to pH5with 0.5M hydrochloric acid and the resulting precipitate filtered offand dried to give the title compound.

¹H NMR (DMSO-d6) δ 7.97 (s, 2H), 7.71 (d, 2H), 7.56 (d, 1H), 7.53 (s,1H), 7.45 (dd, 1H), 7.16 (d, 2H), 5.14 (s, 2H), 3.12 (s, 3H) 2.4 (s, 3H)

APCI+ [M+H] 442

EXAMPLE 37

4-(Acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic acidi) 4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-aceticacid, ethyl ester

The sub-title compound was prepared by the method of Example 5 part (iv)using the product from Example 13 part (i) (330 mg) and4-mercaptobenzonitrile (330 mg). Purified using column chromatography(3% EtOAc/dichloromethane as eluent) to give the sub-title compound (300mg).

¹H NMR (DMSO-d6) δ 9.33 (s, 1H), 8.07 (d, 1H), 7.47 (d, 2H), 7.23 (t,1H), 7.09 (d, 2H), 7.02 (d, 1H), 4.88 (s, 2H), 4.23 (q, 2H), 2.44 (s,3H), 1.93 (s, 3H), 1.28 (t, 3H)

APCI+ [M+H] 408

M.p. 263-5° C.

ii) 4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-aceticacid

The title compound was prepared by the method of Example 1 part (v)using the product from part (ii). The basic solution was adjusted to pH5with 0.5M hydrochloric acid and the resulting precipitate filtered,dried to give the title compound.

¹H NMR (DMSO-d6)

7.63 (d, 2H), 7.37 (d, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 7.07 (d, 2H),5.13 (s, 2H), 2.37 (s, 3H) 1.79 (s, 3H)

APCI+ [M+H] 380

Pharmacological Data Ligand Binding Assay

[³H]PGD₂ was purchased from Perkin Elmer Life Sciences with a specificactivity of 100-210 Ci/mmol. All other chemicals were of analyticalgrade.

HEK cells expressing rhCRTh2/Gα16 were routinely maintained in DMEMcontaining 10% Foetal Bovine Serum (HyClone), 1 mg/ml geneticin, 2 mML-glutamine and 1% non-essential amino acids. For the preparation ofmembranes, the adherent transfected HEKcells were grown to confluence intwo layer tissue culture factories (Fisher, catalogue numberTKT-170-070E). Maximal levels of receptor expression were induced byaddition of 500 mM sodium butyrate for the last 18 hours of culture. Theadherent cells were washed once with phosphate buffered saline (PBS, 50ml per cell factory) and detached by the addition of 50 ml per cellfactory of ice-cold membrane homogenisation buffer [20 mM HEPES (pH7.4), 0.1 mM dithiothreitol, 1 mM FPTA, 0.1 mM phenyl methyl sulphonylfluoride and 100 μg/ml bacitracin]. Cells were pelleted bycentrifugation at 220×g for 10 minutes at 4° C., re-suspended in halfthe original volume of fresh membrane homogenisation buffer anddisrupted using a Polytron homogeniser for 2×20 second bursts keepingthe tube in ice at all times. Unbroken cells were removed bycentrifugation at 220×g for 10 minutes at 4° C. and the membranefraction pelleted by centrifugation at 90000×g for 30 minutes at 4° C.The final pellet was re-suspended in 4 ml of membrane homogenisationbuffer per cell factory used and the protein content determined.Membranes were stored at −80° C. in suitable aliquots.

All assays were performed in Corning clear bottomed, white 96-well NBSplates (Fisher). Prior to assay, the HEK cells membranes containingCRTh2 were coated onto SPA PVT WGA beads (Amersham). For coatingmembranes were incubated with beads at typically 25 μg membrane proteinper mg beads at 4° C. with constant agitation overnight. (The optimumcoating concentrations were determined for each batch of membranes) Thebeads were pelleted by centrifugation (800×g for 7 minutes at 4° C.),washed once with assay buffer (50 mM HEPES pH 7.4 containing 5 mMmagnesium chloride) and finally re-suspended in assay buffer at a beadconcentration of 10 mg/ml.

Each assay contained 20 μl of 6.25 nM [³H]PGD₂, 20 μl membrane saturatedSPA beads both in assay buffer and 10 μl of compound solution or13,14-dihydro-15-keto prostaglandin D₂ (DK-PGD₂, for determination ofnon-specific binding, Cayman chemical company). Compounds and DK-PGD₂were dissolved in DMSO and diluted in the same solvent to 100× therequired final concentration. Assay buffer was added to give a finalconcentration of 10% DMSO (compounds were now at 10× the required finalconcentration) and this was the solution added to the assay plate. Theassay plate was incubated at room temperature for 2 hours and counted ona Wallac Microbeta liquid scintillation counter (1 minute per well).

Compounds of formula (I) have an IC₅₀ value of less than (<) 10 μM.Specifically, example 14 has a pIC₅₀=6.65, example 26 has a pIC₅₀=8.35,and example 34 has a pIC₅₀=9.4.

1. A compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof:

in which: R¹ is one or more substituents independently selected fromNR⁴SO₂R⁵, NR⁴CO₂R⁶, NR⁴COR⁶, NR⁴SO₂NR⁵R⁶, NHSO₂R⁵, NHCO₂R⁶, NHCOR⁶,NHCONR⁴, NHSO₂NR⁵R⁶, or heteroaryl, the latter which may be optionallysubstituted by halogen, CN, OR⁷, C₁₋₃ alkyl (which may be optionallysubstituted by halogen atoms); R² is hydrogen, halogen, CN, SO₂R⁴ orCONR⁵R⁶, CH₂OH, CH₂OR⁴ or C₁₋₇alkyl, the latter group being optionallysubstituted by one or more substituents independently selected fromhalogen atoms, OR⁸ and NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1 or 2; R³ isaryl or heteroaryl each of which is optionally substituted by one ormore substituents independently selected from hydrogen, halogen, CN, OH,SO₂R⁴, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NHSO₂R⁴, NHCOR⁴,NHCO₂R⁴, NR⁷SO₂R⁴, NR⁷CO₂R⁴, NR⁷COR⁴, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁₋₆alkyl, the latter three groups being optionally substituted by one ormore substituents independently selected from halogen atoms, OR⁸ andNR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1 or 2; R⁴ represents aryl, heteroaryl,or C₁₋₆alkyl all of which may be optionally substituted by one or moresubstituents independently selected from halogen atoms, aryl,heteroaryl, OR¹⁰, OH, NR¹¹R¹², S(O)_(x)R¹³ (where x is 0, 1 or 2),CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵, CN, nitro; R⁵ and R⁶independently represent a hydrogen atom, a C₁₋₆ alkyl group, or an aryl,or a heteroaryl, the latter three of which may be optionally substitutedby one or more substituents independently selected from halogen atoms,aryl, OR⁸ and NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵; NR¹⁴SO₂ ¹⁵; CN,nitro, C₁₋₃ alkyl (which may be optionally substituted by halogen atoms;or R⁵ and R⁶ together with the nitrogen atom to which they are attachedcan form a 3-8 membered saturated heterocylic ring optionally containingone or more atoms selected from O, S(O)_(x) where x is 0, 1 or 2, NR¹⁶,and itself optionally substituted by C₁₋₃ alkyl; R⁷ and R¹³independently represent a C₁-C₆, alkyl, an aryl or a heteroaryl group,all of which may be optionally substituted by halogen atoms; R⁸represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl (optionally substitutedby halogen atoms or aryl) an aryl or a heteroaryl group (optionallysubstituted by halogen); each of R⁹ R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵,independently represents a hydrogen atom, C₁-C₆ alkyl, an aryl or aheteroaryl group (all of which may be optionally substituted by halogenatoms); and R¹⁶ is hydrogen, C₁₋₄ alkyl, COC₁-C₄ alkyl or COYC₁-C₄alkylwhere Y is O or NR⁷.
 2. A compound according to claim 1 in which R¹ isNHSO₂R⁴ or NH(CO)R⁴ or heteroaryl (the latter being optionallysubstituted by a C₁₋₃ alkyl group).
 3. A compound according to claim 1or 2 in which R² is C₁ alkyl.
 4. A compound according to claim 3 inwhich R³ is phenyl optionally substituted with halogen or methylsulfone.
 5. A compound according to claim 1 selected from:4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid;3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-aceticacid; 3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-aceticacid;3-[(2-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(3-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(3-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(4-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(2-trifluoromethylphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(8-Quinolinyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;3-[(2-(methylethyl)phenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-aceticacid;5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid;4-(acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid;3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-1-aceticacid;4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid;4-(acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid;3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-indole-1-aceticacid;3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]-1H-indole-1-aceticacid;3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-indole-1-aceticacid;4-(acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid;4-(acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-aceticacid;4-(acetylamino)-2-methyl-3-[[4-(ethylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid;3-[[(4-chlorophenyl)thio]-4-Methylamino)carbonyl]amino]-2-methyl-1H-indole-1-aceticacid;3-[[4-(methylsulfonyl)phenyl]thio]-4-(5-pyrimidinyl)-1H-indole-1-aceticacid2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indole-1-aceticacid4-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-aceticacid2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-thiophenyl)-1H-indole-1-aceticacid5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceticacid2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-aceticacid2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indole-1-aceticacid 4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-aceticacid and pharmaceutically acceptable salts and solvates thereof.
 6. Acompound of formula (I) according to any one of claims 1 to 5 for use intherapy.
 7. A method of treating a disease mediated by prostaglandin D2,which comprises administering to a patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt as defined in claims 1 to
 5. 8. A method of treatment according toclaim 7 wherein the disease is asthma or rhinitis.
 9. The use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in the treatment of a disease mediated by CRTh2. 10.Use according to claim 9 where the disease is asthma.
 11. A process forthe preparation of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof which comprises reaction of acompound of formula (II):

in which R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof, with a compound of formula (IIA):L-CH₂CO₂R¹⁷  (IIA) where R¹⁷ is an alkyl group and L is a leaving groupsuch as a halogen atom, in the presence of a base, and optionallythereafter in any order: removing any protecting group hydrolysing theester group R¹⁷ to the corresponding acid forming a pharmaceuticallyacceptable salt or solvate.
 12. A compound of formula (II) as defined inclaim 11.